Pancreatic cancer is a lethal disease with a poor prognosis and a mortality rate nearly the same as the rate of incidence. Moreover, the disease remains poorly understood. Multiple signal transduction proteins are activated during pancreatic ductal cell carcinogenesis, some may be secondary events, while many others might have critical roles and collectively contribute to the maintenance and the progression of the disease and its responsiveness to therapy. One of the major molecular abnormalities is the overexpression and/or activation of the EGFR protein, which has an incidence of 30-50% of pancreatic cancer cases (1). Evidence indicates that the hyperactive EGF/EGFR duo is important in the disease maintenance and progression (2). Similarly, the overexpression of the c-Src tyrosine kinase occurs in a large percentage of pancreatic adenocarcinoma and is observed to augment EGFR activities during tumorigenesis (3, 4). The over-activity of Src family kinases leads to deregulation of tumor cell growth and survival, disruption of cell-to-cell contacts, and the promotion of migration and invasiveness, and the induction of tumor angiogenesis (4, 5).
Another molecular abnormality is the aberrant activation of Stat3, a member of the Signal Transducer and Activator of Transcription (STAT) family of cytoplasmic transcription factors, which has also been detected in pancreatic tumors and tumor cell lines and been implicated in the disease (6-9). Stat3, as are the other STATs, requires extrinsic tyrosine phosphorylation to become activated and this is induced by growth factor receptors and cytoplasmic tyrosine kinases, such as Src and Janus kinase (Jaks) families (10). In contrast to normal STAT signaling that is transient in accordance with the requirements for normal biological processes, tumor cells harbor aberrant Stat3 activation. Studies show that aberrant Stat3 dysregulates cell growth and survival, promotes tumor angiogenesis, cell migration and invasion, and induces tumor immune tolerance (11-13).
De-regulated signal transduction provides the framework for functional cooperativity and signaling cross-talk that would not only support the malignant phenotype and the disease progression, but also influence the drug responsiveness. Within the context of the concurrent activation of EGFR, Src and Stat3 in pancreatic cancer, the potential for cooperation between EGFR and Src kinases to induce aberrant Stat3 activation and to cooperate in support of the cancer phenotype is a reasonable model to propose. Knowledge of this functional relationship and the collective roles of the proteins in supporting pancreatic cancer can facilitate the design of effective, multiple-targeted therapy for disease. We provide evidence that EGFR and Src promote constitutive Stat3 activation, with a compensatory Stat3 activation mechanism from Jaks, and together support the pancreatic cancer phenotype. Importantly, our study identifies that the concurrent inhibition of aberrant Stat3 and EGFR or Src is more effective in inducing antitumor cell response and pancreatic tumor regression in xenografts.